This invention relates to certain lactones which contain a conjugated triple and double bond functionality. More specifically, this invention relates to certain lactones which have a conjugated triple and double bond with the double bond linked directly to the ether oxygen of the lactone. These compounds are useful as protease inhibitors.
The lactones of this invention are represented by formula I. ##STR2## wherein n is 1-3; R.sup.1, R.sup.2 and R.sup.3 are the same or different and are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, or aryl lower alkyl wherein when aryl is phenyl it is unsubstituted or independently substituted with one or more halo, lower alkyl or lower alkoxy groups; and R.sup.4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trialkylsilyl, aryl or aryl lower alkyl wherein when aryl is phenyl it is unsubstituted or independently substituted by one or more halo, lower alkyl or lower alkoxy groups, excluding those compounds wherein R.sup.1 and R.sup.2 are hydrogen and R.sup.4 is ethyl, propyl or butyl.
Derivatives of 5(E)-(2-iodoalkylidene)-tetrahydro-2-furanone compounds have been used as mechanism-based inhibitors for certain proteases. The synthesis and biological activity of these compounds have been reported by Krafft, G. A. and Katzenellenbogen, J. A., J. Am. Chem. Soc., 103, 5459 (1981); Chakravarty, P. K., et al., J. Biol. Chem., 257, 610 (1982); Sofia, M. J., et al., J. Org. Chem., 48, 3318 (1983); and Daniels S. B., et al., J. Biol. Chem., 258, 15046 (1983). See also the compounds disclosed in Chemical Abstracts 95:198981y, 92:181374t, and 70:93914j.
The subject compounds of this invention are enzyme inhibitors, particularly of proteolytic enzymes including endopeptidases and exopeptidases. Protease inhibitors may be useful in the treatment of a number of diseases including pulmonary emphysema, [Janoff, A., Chest 83 54-58 (1983)] and adult respiratory distress syndrome [Hopewell, P. C. and Murray, J. F. Ann. Rev. Med. 27, 343 (1976)] in which elastase has been implicated; in inflammation in which elastase, collagenase and other lysosomal hydrolases have been implicated; in tumor cell metastasis (in which plasminogen activator, human leukocyte elastase, cathepsin B and related enzymes are thought to play an important role in the pathology [Salo, et al., Int. J. Cancer, 30, 669-673, (1973); Kao, et al., Biochem. Biophys. Res. Comm., 105, 383-389, (1982); Powers, J. C., in "Modification of Proteins," R. E. Feeney and J. R. Whitaker, Eds., Adv. Chem. Ser., 198, Amer. Chem. Soc., Wash., D.C., pp. 347-367, (1982)]; for the treatment of hypertension (angiotensin converting enzyme), (Ondetti, M. A., et al., Science, 196, 441 (1977), in various blood diseases involving venous and arterial thromboembolic disorders [O'Reilly, R. A., in "The Pharmacological Basis of Therapeutics", 6th Edt., Goodman, A. G., Goodman, L. S., Gilman, A., Eds., (1980)]; and in the control of conception, [Zaneveld, L. J. D., et al., Biol. Repro. 20, 1045 (1979)], support a role for acrosin inhibitors as contraceptives.
In addition, this invention relates to a pharmaceutically acceptable formulation comprising at least one compound of formula I in admixture with a pharmaceutically acceptable excipient.
In yet another aspect, this invention relates to a method for inhibiting protease activity which method comprises administering to a mammal a therapeutically effective amount of a compound of formula I either alone or with a pharmaceutically acceptable excipient.
Another aspect of this invention relates to a process for preparing compounds of formula I which comprises treating a terminal alkyne derivative with a compound of formula 2 ##STR3## wherein X is iodo, bromo and chloro and n, R.sup.1, R.sup.2 and R.sup.3 are defined herein about to form a compound of formula I wherein R.sup.4 is not hydrogen; or
treating with silver nitrate and an alkali metal cyanide a compound of formula (3) ##STR4## wherein n, R.sup.1, R.sup.2 and R.sup.3 are defined hereinabove and R.sup.4 is trialkylsilyl to give a compound of formula I wherein R.sup.4 is hydrogen.
The preferred compounds of the invention are those wherein n is 1 or 2 and R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen, lower alkyl, phenyl, phenyl lower alkyl wherein phenyl is unsubstituted or independently substituted with one or more halo, lower alkyl or lower alkoxy groups and R.sup.4 is trialkylsilyl, hydrogen, lower alkyl, phenyl, or phenyl lower alkyl.
More preferred are those compounds wherein n is 1 or 2 and R.sup.1 is hydrogen or lower alkyl, R.sup.2 is hydrogen, lower alkyl, phenyl, or phenyl lower alkyl; R.sup.3 is hydrogen or lower alkyl; and R.sup.4 is trialkylsilyl, hydrogen or lower alkyl.
The most preferred are:
3-benzyl-5(E)-(prop-2-ynylidene)tetrahydro-2-furanone; PA0 3-n-butyl-5(E)-(prop-2-ynylidene)tetrahydro-2-furanone; PA0 3-methyl-3-benzyl-5(E)-(prop-2-ynylidene)tetrahydro-2-furanone; PA0 3-isopropyl-3-benzyl-5(E)-(prop-2-ynylidene)tetrahydro-2-furanone; PA0 3-benzyl-5(E)-(3-methylprop-2-ynylidene)tetrahydro-2-furanone; and PA0 3-benzyl-5(E)-(prop-2-ynylidene)tetrahydro-2-pyrone.
For the purposes of this invention the term "lower alkyl" means a radical of 1-6 carbon atoms, either straight or branched, as exemplified by methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like. Alkyl as used herein has the same meaning as lower alkyl.
Lower alkoxy is an alkoxy group of 1-6 carbon atoms as referred to hereinabove as a lower alkyl radical and is exemplified by methoxy, ethoxy, propoxy, butoxy, and the like.
Lower alkenyl refers to a radical of 2-6 carbon atoms which has one or more double bonds.
The term lower alkynyl refers to a radical of 2-6 carbon atoms having at least one triple bond.
Aryl is an aromatic group which may be phenyl, naphthyl, thiophenyl, furanyl, and the like. Aryl lower alkyl means a radical having an aromatic group substituted on a lower alkyl radical, the lower alkyl radical serving as the bridge between the aromatic group and the remainder of the molecule wherein aryl has the definition given above.
Halo refers to fluoro, chloro, bromo, and iodo.
A pharmaceutically acceptable composition is one safe for use in humans and comprising at least one pharmaceutically acceptable excipient and an amount of a compound of formula I which is not toxic, preferably a therapeutically effective amount.
Administration of the active compounds described herein can be via any of the accepted modes of administration for agents which are systemically active. These methods include oral, parenteral, and otherwise systemic or aerosol forms, including delayed release, implantable formulations.
Depending on the intended mode of administration, the compositions may be in the form of solid, semi-solid, or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unidose forms suitable for single administration of precise dosages. The compositions of this type will include a conventional pharmaceutical carrier or excipient and an active compound of formula I. Such formulations may additionally include other medicinal agents, pharmaceutical agents, carriers, or the like.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Pat. No. 3,710,795.
For systemic administration via suppository, traditional binders and carriers include, e.g. polyalkylene glycols or triglycerides. Such suppositories may be formed from mixtures containing active ingredient in the range of 0.5%-10%; preferably 1-2%.
For aerosol administration, the active ingredient is preferably supplied in finely divided form along with a surfactant and a propellant. Typical percentages of active ingredients are 0.01 to 20% by weight, preferably 0.04 to 1.0%.
The protease inhibition activity of those compounds may be determined by the methods of Krafft, G. A. and Katzenellenbogen, J. A., J. Am. Chem. Soc., 103, 5459 (1981) or any of the other publications set out herein above on page 2.
These compounds will exhibit stereoisomerism when R.sup.1 and R.sup.2 are different. It is to be understood that the representation of formula I provided herein encompasses all stereoisomers whether existing as a racemic mixture or separated into their individual isomers. In this discussion, the racemic mixture will be refered to where appropriate, unless otherwise indicated.
In addition, the compounds of this invention may exist as geometric isomers as represented by formula A and formula B. ##STR5##
Synthesis of the ynenolactone affords primarily the A structure and a minor amount of B.
The geometry of formula A may be altered by UV irradiation the manner of Hammond, G. S., et al., J. Am. Chem. Soc., 86, 3197 (1964), to obtain a photostationary state between formula A and its geometric isomer formula B. Further, E-haloenol lactones of the formula ##STR6## can be isomerized by exposure to acid or silica gel for prolonged periods (Krafft, G. A., and Katzenellenbogen, J. A. J. Am. Chem. Soc., 103, 5459 (1981); the Z-haloenol lactones can then be converted to Z-ynenolactones in the fashion indicated above for the corresponding E forms. Formula I as written herein encompasses both isomers whether present as mixtures or as the individual isomer.